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Departments of 1 Pediatrics (Section of Respiratory Medicine) and 2 Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
METHODS
RESULTS
DISCUSSION
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To study the physiological effects of chronic
intermittent hypoxia on neuronal excitability and function in mice, we
exposed animals to cyclic hypoxia for 8 h daily (12 cycles/h) for
~4 wk, starting at 2-3 days of age, and examined the properties
of freshly dissociated hippocampal neurons in vitro. Compared with
control (Con) hippocampal CA1 neurons, exposed (Cyc) neurons showed
action potentials (AP) with a smaller amplitude and a longer duration and a more depolarized resting membrane potential. They also have a
lower rate of spontaneous firing of AP and a higher rheobase. Furthermore, there was downregulation of the Na+ current
density in Cyc compared with Con neurons (356.09 ± 54.03 pA/pF in
Cyc neurons vs. 508.48 ± 67.30 pA/pF in Con, P < 0.04). Na+ channel characteristics, including activation,
steady-state inactivation, and recovery from inactivation, were similar
in both groups. The deactivation rate, however, was much larger in Cyc
than in Con (at 
100 mV, time constant for deactivation = 0.37 ± 0.04 ms in Cyc neurons and 0.18 ± 0.01 ms in Con
neurons). We conclude that the decreased neuronal excitability in mice
neurons treated with cyclic hypoxia is due, at least in part, to
differences in passive properties (e.g., resting membrane potential)
and in Na+ channel expression and/or regulation. We
hypothesize that this decreased excitability is an adaptive response
that attempts to decrease the energy expenditure that is used for
adjusting disturbances in ionic homeostasis in low-O2 conditions.
sodium channels; excitability; oxygen deprivation
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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A NUMBER OF DISEASE STATES are associated with tissue hypoxia that is intermittent in nature. For example, one of the important consequences of obstructive sleep apnea/hypoventilation syndrome (OSAHS) in both children and adults is a cyclical hypoxia that is engendered by the repetitive upper airway obstruction of OSAHS. This cyclical hypoxia, which generally occurs throughout the night, can repeat itself tens to hundreds of times in a single night and can vary in severity. Arterial oxygen saturations have often been documented to drop to very low levels with every cycle (1). In other diseases, such as in sickle cell disease, hypoxia and ischemia are rather cyclical but the periodicity may differ from that in OSAHS.
The effects of intermittent hypoxia on neural function and behavior are ill defined. Although there has been a substantial amount of work in the past two decades delineating the cellular and molecular mechanisms of sensing the lack of oxygenation and the mechanisms of injury, repair, or survival, there are still many important questions that are unanswered. For example, it is controversial whether a previous exposure to hypoxia renders neurons more or less susceptible to subsequent hypoxic stress, because subsequent responsiveness may depend on exposure paradigm (9). On the one hand, because repetitive hypoxia in OSAHS can be severe and can occur over prolonged periods of time, as in OSAHS, it is possible that it plays an important role in producing central neuronal sublethal damage or degeneration. On the other hand, it is possible that central neurons may adapt during the exposure to lessen injury and to survive. Therefore, we ask in this work whether cyclical hypoxia induces injury to central neurons and, if so, by what mechanisms. To address these questions, we have recently developed methods to study cyclical hypoxia in rodents (mice) and determine the cellular and molecular mechanisms that can lead to cell injury (or adaptation and survival) under such conditions. Because the impact of cyclical hypoxia may depend on the level of central nervous system maturation and the magnitude of exposure to hypoxia, we have started this work by studying mice in early life. In addition, we have focused our work on the hippocampus because this has been a well-studied region and because hippocampal neurons show increased sensitivity to low-O2 conditions (4). In this work, we have therefore determined how the electrophysiological and membrane properties of neurons harvested from exposed animals differ from those of naive ones.
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METHODS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Cyclic Hypoxia
A computer-controlled chamber was developed in our laboratory for the induction and maintenance of cyclic hypoxia. This chamber (volume
80 liters) allowed us to expose mice to cyclic hypoxia. The
chamber can hold up to three mouse cages simultaneously. The times of
the on-off cycle durations were automatically controlled by valves, an
IBM-compatible computer equipped with an analog-to-digital converter,
and a software written in BASIC on an IBM-compatible computer. Oxygen
concentration in the chamber was measured by an oxygen meter (OM200,
Cameron Instrument). At the age of 2-3 days, mice were placed in
the chamber with their mother. Cyclic hypoxia was induced daily to mice
for 8 h during the day; mice were placed in room air for 16 h
at night. Each hypoxic duration of each cycle was ~2 min with a nadir
of fractional inspired O2 of ~7.5%, and the
"off-time" (normoxia) consisted of ~3 min. Mice were exposed to
cyclical hypoxia for ~4 wk. Mice were not weaned and stayed with
their mother until the time for death. Eighteen mice were exposed to
hypoxia, and thirteen others were used for controls. Almost 100% of
the exposed mice survived the ~4 wk of exposure. Pregnant mice were
all purchased from Charles River, and pups were born, raised, and
cyclic hypoxically treated at Yale.
Preparation of CA1 Cells
Mice were obtained from Charles River. Mice 25-30 days old were used, and their hippocampi were removed and sliced into 7-10 transverse sections 400 µm thick. The slices were immediately transferred to a container with 25 ml of fresh, oxygenated, and slightly stirred HEPES buffer at room temperature. After 30 min of exposure to trypsin (0.08%) and 20 min of protease (0.05%) digestion, the slices were washed several times with HEPES buffer and left in oxygenated solution. The CA1 region was then dissected out and triturated in a small volume (0.25 ml) of HEPES buffer. The Yale Animal Care and Use Committee approved these studies.Electrophysiological Recording and Solutions
Electrodes were pulled on a Flaming/Brown micropipette puller (model P-87, Sutter Instrument) from filamented borosilicate capillary glass (1.2 mm OD, 0.69 mm ID, World Precision Instruments). The electrodes were fire polished, and resistances were 2-5 M
for
voltage-clamp experiments and 7-9 M for current-clamp
experiments in the solutions listed below. Resting membrane potential
(Vm) and action potentials (AP) were recorded in
the current-clamp mode. Input resistance was measured at 70
mV as a slope of the current trace evoked by a ramp voltage from 160
to 100 mV in the voltage-clamp mode. The slope was derived from least
squares regression analysis for 100 data points between voltage and
current. Current traces in voltage clamp were leak subtracted. Junction nulls were performed for each individual cell with the Axopatch 1C amplifier.
For the current-clamp experiments, the external HEPES solution bathing neurons contained (in mM) 130 NaCl, 3 KCl, 1 CaCl2, 1 MgCl2, 10 HEPES, and 10 glucose, adjusted pH 7.4 with NaOH. The pipette solution contained (in mM) 138 KCl, 0.2 CaCl2, 1 MgCl2, 10 HEPES (Na+ salt), and 10 EGTA, adjusted pH 7.4 with Tris. The external solutions for the voltage-clamp experiments contained the same salts as in the current-clamp experiments, except for 10 mM tetraethylammonium, 5 mM 4-aminopyridine, and 0.1 mM CdCl2 that replaced equimolar concentrations of NaCl. The internal pipette solution for the voltage-clamp experiments was also similar to the internal solution for the current-clamp experiments, except for CsF or CsCl instead of KCl. The HEPES-buffered solutions for the enzymatic preparation and trituration of the CA1 cells contained (in mM) 125 NaCl, 3 KCl, 1.2 MgSO4, 1.25 NaH2PO4, 30 HEPES, and 10 glucose. Osmolarity of all solutions was adjusted to 290 mosM of the mean. All recordings were performed at room temperature (22-24°C). One-tailed Student's t-test was performed for mean comparisons. Numbers in the text and in the figures are given as means ± SE. All chemicals were purchased from Sigma Chemical.
Recording Criteria
Morphological criteria. CA1 cells were used if they had a smooth surface, a three-dimensional contour, and were pyramidal in shape. Similar criteria have been used by our laboratory (2) and others (5) on freshly triturated neurons. The CA1 cells studied were obtained from 25- to 30-day-old mice.
Electrophysiological criteria.
1) Neurons were considered for recording if the seal
resistance was >5 G. 2) Only neurons with a holding
current of <0.1 nA (command potential 100 mV) were used in the
study. 3) Series resistance was <10 M in neurons
studied. The series resistances were compensated at the 90% level with
the Axopatch 1C amplifier (Axon Instruments). Under these conditions,
the error caused by uncompensated series resistances was <2.8 mV. To
obtain adequate voltage clamp and minimize the space clamp problem,
only small neurons with short processes were used in sodium
current measurements. In addition, only cells with
current-voltage relationship curves that were smoothly graded
over the voltage range of activation (approx. 50 to 10 mV)
were used, as our laboratory has done in the past (2, 8).
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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Neuronal Properties and Membrane Excitability
All control (Con) CA1 neurons fired AP when they were held at75
mV and given depolarizing currents in the current-clamp mode. However,
not all CA1 neurons from exposed mice (Cyc) fired AP under the same
conditions. Of 23 Cyc neurons, 2 did not show any AP even with 1 nA
command current injected; the other 8 neurons had very small AP (the AP
amplitude was under 10-20 mV, without apparent shoulder or rapid
uprising change) even when injected with a current as large as
300-500 pA. The other 13 Cyc neurons fired AP when evoked but not
spontaneously. We also found that 7 of 12 Con neurons fired spontaneous
AP. Because Cyc CA1 neurons seemed less excitable than the Con ones, we
systematically determined the rheobase. Indeed, this was substantially
larger in the Cyc neurons than in Con neurons (Fig.
1). Stepping all neurons from the same
Vm (75 mV) in the current-clamp mode, the amount of current required to generate one AP was 24.25 ± 5.73 pA
(n = 10) in Con but 146.54 ± 27.88 pA
(n = 13, not including the above-mentioned 10 Cyc
neurons, P = 0.0005) in the Cyc neurons (Fig.
1C). The number of AP in a 150-ms command duration was
1.31 ± 0.17 (n = 13) for Cyc neurons and
2.58 ± 0.72 (n = 12, P = 0.04)
for Con neurons. AP characteristics were also compared between the two groups. Although the threshold of AP was not different between the two
groups (56.33 ± 2.53 mV, n = 11, in Con neurons
and 52.19 ± 2.77 mV, n = 8, in Cyc neurons),
the AP amplitude was much smaller in Cyc neurons than in Con neurons
(51.76 ± 12.64 mV, n = 8, vs. 85.40 ± 5.79 mV, n = 11, Fig. 2,
A-C, P = 0.008).
Furthermore, AP duration, measured halfway between the threshold and AP
peak, was much longer in Cyc than in Con neurons (2.36 ± 0.37 ms,
n = 8, vs. 1.66 ± 0.17 ms, n = 11, P = 0.04). The time from the stimulation to the
peak of the first AP was also much longer in Cyc than in Con neurons
(9.28 ± 1.62 ms, n = 8, vs. 4.26 ± 0.42 ms,
n = 11, P = 0.002). Cyc CA1 neurons had
a more depolarized membrane potential than Con neurons (Vm:
33.91 ± 2.89 mV, n = 10, vs. 44.09 ± 2.97 mV, n = 11, P = 0.01) and
somewhat lower input resistance (838.42 ± 282.08 M,
n = 14, vs. 908.18 ± 298.27 M,
n = 10) in Con neurons.
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Na+ Current Magnitude
Because neuronal excitability is largely dependent on the characteristics and magnitude of Na+ channels, especially when neurons were stepped from the same Vm, we examined the Na+ channel properties in both groups of neurons. Under voltage clamp, steps from a holding potential of130
to 20 mV evoked an inward current that reached a peak in less than 1 ms and decayed quickly to zero current. TTX (1 µM) blocked the
current almost totally. On the basis of its voltage dependency,
characteristics, and TTX sensitivity, we considered this to be a
voltage-sensitive fast Na+ current. The average peak
Na+ current in Cyc neurons was 1,622.70 ± 258.92 pA
(n = 26), compared with a much larger peak
Na+ current in Con of 3,266.57 ± 576.64 pA
(n = 19, P = 0.003) (Fig. 3A). Because the difference in
current magnitude between both groups of neurons could be related to
neuronal surface area (as indicated by whole cell capacitance
measurements with 6.38 ± 0.55 pF, n = 19, in Con
neurons and 4.42 ± 0.29 pF, n = 26, in Cyc neurons, P = 0.002), we normalized the peak current to
surface area using capacitance. The Na+ current density was
also much smaller in Cyc neurons (356.09 ± 54.03 pA/pF,
n = 26) compared with Con neurons (491.15 ± 58.56 pA/pF, n = 19, P = 0.05) (Fig.
3B).
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Na+ Current Characteristics
We next examined the characteristics of the Na+ current to determine whether there are other differences between the Cyc and Con neurons that could be important in determining excitability.Activation.
With CA1 neurons held at 130 mV, depolarizing voltages were given
from 70 to +80 mV with 10-mV increments. For both groups of neurons,
the threshold for Na+ channel activation was 60 mV, and
the Na+ current reached a peak at 20 mV. The midpoint for
the voltage-conductance relation was almost the same in both groups
(39.74 mV for Con neurons, n = 8, and 43.55 mV,
n = 8, for Cyc neurons). Similarly, the activation
slope factors were not different in both groups of neurons (Fig.
4A).
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Steady-state inactivation.
Steady-state inactivation of the Na+ current was studied
using a prepulse potential from 130 to 20 mV and then stepping
Vm to 20 mV. There was no difference also in the
steady-state inactivation characteristics (Fig. 4A). The
midpoint of steady-state activation was 63.07 mV (slope factor 7.11, n = 8) and 60.11 mV (slope factor = 9.76, n = 17) for Con and Cyc neurons, respectively.
Recovery from inactivation. To examine the recovery from inactivation, we used a two-pulse protocol with increased interval in between the two pulses. The recovery from inactivation in both groups of neurons was almost identical (Fig. 4B). The time constant for recovery in Con was 1.86 ± 0.26 ms (n = 11) and 1.83 ± 0.30 ms (n = 6) in Cyc neurons.
Deactivation characteristics.
We also examined the deactivation properties, i.e., the transition from
the open to the resting closed state for both groups of neurons. We
held CA1 neurons at 100 mV, depolarized them for 1 ms to 10 mV, and
repolarized them to 70 or 100 mV (Fig. 5B, inset). The averaged time constant for deactivation
(
d) at 100 mV was larger for Cyc neurons (0.37 ± 0.04 ms, n = 17) than that for Con neurons (0.18 ± 0.01 ms, n = 5, P = 0.008) (Fig.
5C). At 70 mV, the results
showed similar differences between both groups (0.89 ± 0.19 ms,
n = 17 for Cyc and 0.29 ± 0.05 ms,
n = 5, for Con, P = 0.05).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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In this study, we have made an important observation regarding the excitability of CA1 neurons after exposure to chronic intermittent hypoxia in vivo. CA1 neurons are much less excitable after cyclic hypoxia treatment than are control neurons. Furthermore, we have presented data about potential mechanisms that can explain the differences in excitability between Cyc and Con CA1 neurons.
It is clear from our data that Cyc CA1 hippocampal neurons are much less excitable than Con neurons. The amplitudes of AP in Cyc neurons were much smaller, the rheobase much higher, and 43% (10 of 23) of Cyc neurons did not even fire AP on stimulation and no Cyc neurons had spontaneous AP.
There are several reasons for the Cyc neurons to be less excitable than
their counterpart Con ones. First, the likelihood of a depolarization
block in Cyc neurons is higher than in Con neurons. Because Cyc neurons
were more depolarized (33.91 mV) than Con neurons (44.09 mV) at
rest and because the AP threshold was rather similar (52.19 mV and
56.33 mV for Cyc and Con neurons) in both groups, the difference
between the Vm and the AP threshold was larger
for the Cyc neurons (~18 mV) than for the Con neurons (~12 mV).
Second, the Na+ current density was significantly (~30%)
lower in the Cyc neurons than in Con neurons. This difference in
Na+ channel density can certainly be an important
contributor in explaining the difference in excitability between the
two groups of neurons. It should also be noted that this difference
between the two groups in terms of the Na+ current is an
underestimate because there were a number of Cyc neurons that did not
fire AP and may not have had enough Na+ channels or whose
Na+ channels may not have been in an "activatable"
state to fire AP. Third, it is also possible that the slower
deactivation time constant of the Na+ channels in Cyc
neurons is a factor in lowering the firing activity in these neurons.
Because 1) the deactivation rate is an index of the time
taken by the Na+ channels to go back to the closed state
(after they had been briefly open, without going into the inactivation
state), 2) this time is longer in Cyc than Con, and
3) slowing the process of deactivation can slow the
repolarization of each AP (3, 6, 7), the firing frequency
can be reduced. This was found indeed in these Cyc neurons compared
with Con neurons as the number of AP in Con was double that in Cyc in
150-ms test duration. Although there are potentially several factors
(as indicated above) that can explain a lowering in firing frequency in
these neurons, the decreased rate of deactivation might also be one of
them. Deactivation rates have been shown to respond to a variety of
factors such as second-messenger systems (e.g., protein kinase
A) and microenvironmental changes (e.g., toxins). The reasons
for the differences between Cyc and Con are not clear but could be
related to changes in second messenger systems.
Our data, which demonstrate that the whole cell Na+ current is smaller in Cyc neurons than in Con neurons, do not allow us to clearly differentiate between the various possibilities that led to this reduction in Na+ channel current. For example, there are potentially three different scenarios: the Na+ channel expression in the plasma membrane may have been lowered with cyclic hypoxia, the single-channel ionic conductance may have decreased, or the open probability of the channel may have been reduced. Our data do not separate among these three possibilities.
One of the ideas that we would like to highlight in this paper is that the decreased excitability in neurons that have been exposed to cyclical hypoxia may have a beneficial outcome. We argue that this decreased neuronal excitability may lead to a decrease in energy expenditure, albeit at the cost of a decrease in communication among neurons and glia. This decrease in energy expenditure is likely to be important in cell adaptation and survival because reducing ATP levels may lead to cell injury and death. Hence it is possible that the cellular "strategy" is to decrease communication for the sake of survival. What is not clear at present is whether hippocampal neurons have decreased their metabolic rate and how was this achieved. In addition, it would seem that, at a cost of altering or reducing the function of neurons, the cellular strategy would seem to favor survival over function. Depending on cell type and cell region, this may have major effects on memory, cognition, or autonomic activities.
Although the treatment of cyclic hypoxia altered a number of characteristics of Na+ channels, this treatment was also fairly selective. For example, the voltage-conductance relationship, the steady-state inactivation, and the recovery from inactivation were almost exactly the same in both the experimental and the control mice. How and why cyclic hypoxia induces specific changes in the Na+ channel characteristics and possibly its expression are not clear to us at present.
One additional interesting finding in this work was that the capacitance in Cyc neurons was significantly smaller than that in Con neurons. Although there could have been a bias in the selection of these cells, it is possible that cells in Cyc mice were smaller in size than their counterparts in Con mice. This may not be surprising, given that other investigators have shown that repeated hypoxia induces structural changes in hippocampal CA1 neurons such as a reduction in the number of dendritic branchings (10). Hence, it would be useful in the future to characterize quantitatively the morphological changes in these neurons because these alterations may have profound effects on cell-cell communications.
In summary, we have been able to show that mice exposed to cyclic hypoxia have an overall lower hippocampal neuronal excitability. This decreased excitability can be explained by 1) a downregulation of the Na+ current and alterations in the channel characteristics, including deactivation, and 2) alterations observed in the passive properties of CA1 neurons. This investigation documents the existence of an important functional link between cyclic hypoxia and the voltage-sensitive Na+ channel. The importance of this link is related to the idea that the changes in the Na+ channel documented in this work may be critical for the decreased excitability of neurons and their metabolic demands.
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ACKNOWLEDGEMENTS |
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We thank Dr. Hang Yao for participating the earlier work. We also thank Ralph Garcia and Aaron Hochberg for invaluable technical assistance.
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FOOTNOTES |
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This work was supported by National Institutes of Health Grants PO1HD, 32573, RO1 NS-35918, and RO1 HL-66327.
Address for reprint requests and other correspondence: G. G. Haddad, Dept. of Pediatrics, Section of Respiratory Medicine, Rm. 508, Yale Univ. School of Medicine, 333 Cedar St., New Haven, CT 06510 (E-mail: gabriel.haddad{at}yale.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Received 14 February 2001; accepted in final form 19 April 2001.
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REFERENCES |
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TOP
ABSTRACT
INTRODUCTION
METHODS
RESULTS
DISCUSSION
REFERENCES
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